Macrophage heterogeneity and cholesterol homeostasis: Classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL

Abstract

Macrophages are centrally involved during atherosclerosis development and are the predominant cell type that accumulates cholesterol in the plaque. Macrophages however, are heterogeneous in nature reflecting a variety of microenvironments and different phenotypes may be more prone to contribute towards atherosclerosis progression. Using primary human monocyte-derived macrophages, we sought to evaluate one aspect of atherogenic potential of different macrophage phenotypes by determining their propensity to associate with and accumulate oxidized low density lipoprotein (oxLDL). Classically-activated macrophages treated simultaneously with interferon γ (IFNγ) and tumour necrosis factor α (TNFα) associated with less oxLDL and accumulated less cholesterol compared to untreated controls. The combined treatment of IFNγ and TNFα reduced the mRNA expression of CD36 and the expression of both cell surface CD36 and macrophage scavenger receptor 1 (MSR1) protein. Under oxLDL loaded conditions, IFNγ and TNFα did not reduce macrophage protein expression of the transcription factor peroxisome proliferator-actived receptor γ (PPARγ) which is known to positively regulate CD36 expression. However, macrophages treated with IFNγ did prevent the PPARγ-specific agonist rosiglitazone from upregulating cell surface CD36 protein expression. Our results demonstrate that the observed reduction of cholesterol accumulation in macrophages treated with IFNγ and TNFα following oxLDL treatment was due at least in part to reduced cell surface CD36 and MSR1 protein expression.

Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice

“…It has been shown that M1 activated macrophages demonstrate reduced foam cell formation in response to oxLDL 36, 87 and that Mox activated macrophages have attenuated phagocytosis and efferocytosis 39 . It would thus have been reasonable to speculate that IGF1R deficiency, which enhances the proinflammatory phenotype as well as Mox marker expression levels, could lead to reduced foam cell formation.…”

The role of CD36 receptor in the pathogenesis of atherosclerosis

“…This combined treatment of IFN-γ and TNF-α in mRNA reduced the CD36 expression on macrophages. 33 Recent studies indicate that human neutrophil peptides (HNPs) take part in atherosclerosis development. 34,35 Quinn et al 36 suggest that the HNP induces increase of CD36 expression in the surface of macrophages and as a result contributes to the increased amount of foam cell formation.…”

FAK and PYK2 are specifically associated with the activated phagocytic receptor complexes from human U937 cells.

“…In particular, participation of focal adhesion kinases and Rho GEFs, which signals CD36 to perform degradation, active migration internalization and binding regulation (Prieto et al, 1994). CD36 can be reduced considerably with treatment by tumor necrosis factor α (TNF-α) and interferon γ combined (Chu et al, 2013). FAK activates actin polymerization and is thought to have an impact on macrophage aggregation and foam cell formation in the arterial intima (Park et al, 2009).…”